Senescence, an underappreciated cell dormancy phenotype that occurs upon treatment with many cytotoxic drugs, represents a new paradigm in drug development. This phenotype imparts detrimental effects on the local tumor microenvironment, primarily due to pro-inflammatory properties that drive resistance and metastatic progression. Thus, there is an unmet need to screen novel anti-cancer drugs for their senescence inducing potential. Another mode of chemotherapy-related dormancy that also needs to be modeled in modern drug development is the enrichment of tumor initiating cells with successive rounds of treatment. Collectively, both forms of tumor dormancy equate to poor clinical response that necessitates second- and third-line treatment leading to irreversible toxicities that negatively impact quality of life and eventually render patients ineligible for continued treatment. Thus, the design and evaluation of potent, metabolically stable, novel anti-cancer drugs selected to circumvent senescence will have high impact for the treatment of recalcitrant cancers in the first- line and metastatic setting. This project will evolve our previos studies with a microtubule inhibitor, discodermolide, to synthesize a series of novel analogues that have modifications of the lactone ring and diene moieties that we hypothesize influence tumor cell kill and senescence induction in cells. The overall goal of this program is to select lead compounds that have: (A) a low propensity to induce senescence, (B) high induction of tumor cell death in chemorefractory cell types, such as tumor initiating cells, and (C) minimal toxicity, as determined from measures of cardiopulmonary function and histology, nerve conduction, and neuropsychology. These studies will be applied to cell-based and whole-animal models of recalcitrant tumor types, namely triple negative breast cancer, non-small cell lung cancer and serous ovarian cancer. Finally, in-depth testing of two lead candidates in mouse models of patient-derived cancer will enable selection of a highly efficacious novel anti-tumor agent suitable for first in-human testing. This project brings together a diverse team of experts committed to evolving the rational design and synthesis of novel microtubule targeting drugs to alleviate the suffering and mortality of cancer patients.